7-beta analogs of orvinols

Abstract

The application is directed to compounds of Formula I (I) and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 1a , R 1b , X, Y, Z, G, Q, W 1 and W 2 are defined as set forth in the specification. The invention is also directed to use of the compounds of Formula I and the pharmaceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein
 the 7β-epimer compound of Formula I is present in an enantiomeric excess relative to any 7α-epimer compound, wherein: 
 R 1  is selected from the group consisting of hydrogen, (C 1 -C 10 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 1 -C 10 )alkoxy, (C 3 -C 12 )cycloalkyl, (C 4 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, and ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-; any of which is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of (C 1 -C 6 )alkyl, OH, halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(C 1 -C 6 )alkyl-COOR 7 , —COOR 7 , NH 2 , —NH(C 1 -C 6 )alkyl, —NR 9 R 10 , CN, —CONR 9 R 10 , —NR 9 COR 10 , —SR 11 , (5- to 12-membered)carbocyclic ring, (5- to 12-membered)heterocycle, phenyl, and benzyl; 
 Z is —(CH 2 ) m —, optionally substituted with 1 or 2 (C 1 -C 6 )alkyl; 
 Y is —(CH 2 ) n —CH or a direct bond, provided that when Y is a direct bond then W 2  is absent and W 1  is attached to G; 
 G is selected from the group consisting of —O—, —OC(═O)—, —C(═O)—, —NR 3 —, —S—, —SO—, and SO 2 —; 
 W 1  and W 2  are each independently selected from the group consisting of hydrogen, (C 1 -C 10 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, NH 2 , —NH(C 1 -C 6 )alkyl, CN, —CONR 5 R 6 , —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, (C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, (C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, (C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; any of which is optionally substituted with one or two substituents each independently selected from the group consisting of OH, (═O), halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy, ((C 1 -C 6 )alkoxy)CO(C 1 -C 6 )alkoxy-, —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-NH(C 1 -C 6 )alkyl-R 14 , CN, SH, —OR 4 , —CONR 5 R 6 , —(C 1 -C 6 alkyl)-CO—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, —NH—SO 2 (C 1 -C 6 )alkyl, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—CO—(C 1 -C 6 )alkyl, —NH—CO—NH 2 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 12-membered)aryl, —NH—C(═O)—(C 1 -C 6 )alkyl-(6- to 12-membered)aryl, —NH—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 , (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, (6- to 12-membered)aryloxy, —(C 1 -C 6 )alkoxyC(O)NR 5 R 6 , —NH—(C 1 -C 6 )alkylC(O)—NR 5 R 6 , —C(O)NH—(C 1 -C 6 )alkyl-COOR 7 , ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-, provided that W 1  is other than hydrogen when Y is direct bond and G is O; 
 Q is selected from the group consisting of OH, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkyl, (C 3 -C 12 )cycloalkyl, (6- to 12-membered)aryl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —(OCH 2 CH 2 ) s —OH, —O(C═O)R 9 , —O—(C 1 -C 6 )alkyl-COOR 7 , —NH—(C 1 -C 6 )alkyl-COOR 7 , —O—C(O)—(C 1 -C 6 )alkyl-C(O)OR 7 , —NH—C(O)—(C 1 -C 6 )alkyl-C(O)OR 7 , —O—(C 1 -C 6 )alkyl-C(O)NR 9 R 10 , —NH—(C 1 -C 6 )alkyl-C(O)NR 9 R 10 , —O—C(O)—(C 1 -C 6 )alkyl-C(O)NR 9 R 10 , —NH—C(O)—(C 1 -C 6 )alkyl-C(O)NR 9 R 10 , and R 14 ; 
 R 1a  and R 1b  are each independently selected from the group consisting of hydrogen, (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 1 -C 10 )alkoxy, OH, hydroxy(C 1 -C 6 )alkyl-, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(C 1 -C 6 )alkyl-C(═O)—(C 1 -C 6 )alkoxy, —(C 1 -C 6 )alkoxy-C(═O)—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-CN, —(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkoxy-, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, (C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkoxy-, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkoxy-, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkoxy-, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkoxy-, and ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, or 
 R 1a  and R 1b  together form (═O); 
 X is selected from the group consisting of OH, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, halogen, NH 2 , —NR 2 (C═O)R 12 , —CONR 12 R 13 , —(C 1 -C 6 )alkyl-CONH 2 , —(C 1 -C 6 )alkyl-COOH, COOH, —O—(C 1 -C 6 )alkyl-COOH, —O—(C 1 -C 6 )alkyl-CONH 2 , (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(OCH 2 CH 2 ) s —OH, —(CH 2 ) p CHOHCH 2 OH, CN, —NH—SO 2 R 9 , (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkoxy-, (5- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkoxy-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkoxy-, (3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkoxy-, (7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkoxy-; or 
 X is —O-PG, wherein PG is a hydroxyl protecting group; 
 R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), hydroxy(C 1 -C 6 )alkyl-, (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, (C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, (C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, (C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
 R 3  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 10 )alkoxy, (C 3 -C 12 )cycloalkyl, (C 3 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, ((C 3 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —C(═O)(C 1 -C 6 )alkyl, and —SO 2 (C 1 -C 6 )alkyl; 
 R 4  is selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), hydroxy(C 1 -C 6 )alkyl-, (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, (C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, (C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, (C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
 R 5  and R 6  are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, ((C 3 -C 8 )cycloalkyl)-(C 1 -C 6 )alkyl-, —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —CONH 2 , and (C 1 -C 6 )alkyl-CONH—; or 
 R 5  and R 6  together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle; 
 R 7  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 12 )cycloalkyl, (C 4 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, and ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-; 
 R 9  and R 19  are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 10 )alkoxy, (C 3 -C 12 )cycloalkyl, (C 3 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, and ((C 3 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-; 
 R 11  is selected from the group consisting of hydrogen, (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 1 -C 10 )alkoxy, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, (C 4 -C 12 )cycloalkenyl, and ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-; 
 R 12  and R 13  are each independently selected from the group consisting of hydrogen, (C 1 -C 10 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, (C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, (C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, (C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, (C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)(C 1 -C 6 )alkyl-, (7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; any of which is optionally substituted with one or two substituents each independently selected from the group consisting of OH, (═O), halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, NH 2 , —NH(C 1 -C 6 )alkyl, CN, SH, OR 4 , —CONR 5 R 6 , —COOR 7 , (C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
 R 14  is selected from the group consisting of —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkyl-C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —CONH 2 , and (C 1 -C 6 )alkyl-CONH—; 
 m is an integer 1, 2, 3, 4, 5, or 6; 
 n is an integer 0, 1, 2, 3, 4, 5 or 6; 
 p is an integer 0, 1 or 2; and 
 s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. 
 
     
     
         2 . The compound of  claim 1  having the Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein the 7β-epimer compound of Formula II is present in an enantiomeric excess relative to any 7α-epimer compound, and wherein R 1 , R 1a , R 1b , X, Z, G, Y, W 1 , W 2 , and Q are as defined in  claim 1 . 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein R 1a  and R 1b  both are hydrogen, W 2  is hydrogen, Y is (CH 2 ) n —CH, and n is 0, represented by Formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein the 7β-epimer compound of Formula III is present in an enantiomeric excess relative to any 7α-epimer compound, and wherein G 1  is —O— or —NH—, and R 1 , X, Z, W 1 , and Q are as defined in  claim 1 . 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is selected from the group consisting of hydrogen, methyl, cyclopropylmethyl, —CH 2 CH═CH 2 , —CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 C(O)OH, CH 2 C(O)OH, CH 2 C(O)NH 2 , and —CH 2 -tetrazolyl. 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein G is —O—. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein G is —NR 3 — and R 3  is selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl. 
     
     
         13 . The compound of  claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein G is —NH— or —N(CH 3 )—. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Q is selected from the group consisting of OH and OCH 3 . 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from the group consisting of OH, OCH 3 , F, Br, —COOH, —CONH 2 , —OCH 2 CH 2 OH, —CH═CH 2 , —NHSO 2 CH 3 , —NHC(O)CH 3 , CN, —(OCH 2 CH 2 ) s OCH 3 , wherein s is selected from 1, 2, 3, 4, 5, or 6, —CH(OH)CH 2 OH, —OCH 2 -tetrazolyl, —OCH 2 C(O)NH 2 , —CH 2 CH(OH)CH 2 OH, tetrazolyl, and NH 2 . 
     
     
         20 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of W 1  and W 2  is (C 1 -C 10 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 12 )cycloalkyl, (C 4 -C 12 )cycloalkenyl, (C 6 -C 14 )bicycloalkyl, (C 8 -C 20 )tricycloalkyl, (C 7 -C 14 )bicycloalkehyl, (C 8 -C 20 )tricycloalkenyl, (6- to 12-membered)aryl, ((6- to 12-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, (3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, (7- to 12-membered)bicycloheterocycle, or ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; any of which is optionally substituted with one or two substituents each independently selected from the group consisting of OH, (═O), halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, phenyl, benzyl, NH 2 , —NH(C 1 -C 6 )alkyl, CN, SH, OR 4 , —CONR 5 R 6 , and —COOR 7 . 
     
     
         21 . (canceled) 
     
     
         22 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein —Y(W 1 )(W 2 ) is —CH 2 -(5- to 12-membered)heteroaryl, which is optionally substituted with one or two substituents each independently selected from the group consisting of OH, (═O), halo, —C(halo) 3 , —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 alkyl)-CO—NR 5 R 6 , (C 1 -C 6 )alkyl, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkyl-CO—OR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy-COOR 7 , (6- to 12-membered)aryl, (6- to 12 membered)aryloxy, —CONR 5 R 6 , —COOR 7 , —NH—SO 2 (C 1 -C 6 )alkyl, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—CO—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 12-membered)aryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, —NH—CO—NH 2 , —NH—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxyC(O)NR 5 R 6 , —NH—(C 1 -C 6 )alkylC(O)—NR 5 R 6 , —C(O)NH—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-CO—OR 7 , and —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 . 
     
     
         23 . The compound of  claim 1 , wherein —Y(W 1 )(W 2 ) is —CH 2 -(6- to 12-membered)aryl, which is optionally substituted with one or two substituents each independently selected from the group consisting of OH, (═O), halo, —C(halo) 3 , —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 alkyl)-CO—NR 5 R 6 , (C 1 -C 6 )alkyl, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkyl-CO—OR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy-COOR 7 , (6- to 12-membered)aryl, (6- to 12-membered)aryloxy, —CONR 5 R 6 , —COOR 7 , —NH—SO 2 (C 1 -C 6 )alkyl, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—CO—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 12-membered)aryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, —NH—CO—NH 2 , —NH—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxyC(O)NR 5 R 6 , —NH—(C 1 -C 6 )alkylC(O)—NR 5 R 6 , —C(O)NH—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-CO—OR 7 , and —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 . 
     
     
         24 - 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 or 2. 
     
     
         27 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Y is (CH 2 ) n —CH and n is 0 or 1. 
     
     
         28 - 29 . (canceled) 
     
     
         30 . The compound of  claim 1  having the Formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein the 7β-epimer compound of Formula IV is present in an enantiomeric excess relative to any 7α-epimer compound, and wherein
 G is —O—, —OC(═O)—, —C(═O)—, —NH—, —S—, —SO—, or —SO 2 —; 
 R 15  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         R 16  is selected from the group consisting of hydrogen, halogen, —(C 1-4  alkyl)(halo) 3 , —O(C 1-4  alkyl)(halo) 3 , phenyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, 1,2-dihydroxyethyl, C(O)N H 2 , —OCH 2 COOH, —NHCOOH, —OCH 2 C(O)OCH 3 , imidazolyl, —NHC(O)NH 2 , —NHC(O)NHCH 3 , —NHC(O)-phenyl, and C(═NH)NH 2 . 
       
     
     
         31 . The compound of  claim 30 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is CH 3  or cyclopropylmethyl, X is selected from the group consisting of OH and (C 1-4 )alkoxy, Q is selected from the group consisting of OH and (C 1-4 )alkoxy, G is —O— or —NH—, and R 1a  and R 1b  are both hydrogen. 
     
     
         32 . The compound of  claim 1 , selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the percent enantiomeric excess of the 7β-epimer is at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%. 
     
     
         35 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         36 - 39 . (canceled) 
     
     
         40 . A method of treating pain in a patient, comprising administering an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to the patient in need of such treatment or prevention. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 40 , wherein said pain is acute pain, chronic pain or surgical pain, wherein said chronic pain is neuropathic pain, postoperative pain, or inflammatory pain. 
     
     
         43 - 44 . (canceled) 
     
     
         45 . A method of modulating one or more opioid receptors in a patient, comprising administering to the patient an effective amount of a compound as claimed in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         46 . The method of  claim 45 , wherein μ- or κ-opioid receptor is modulated, or both the μ- and κ-opioid receptors are modulated. 
     
     
         47 - 73 . (canceled)